CagriSema

CagriSema: what the published research shows

Compiled by NADA-Labs from the peer-reviewed literature cited below. No own study data.

CagriSema is the name used in the trial literature for the combination of the long-acting amylin-receptor agonist CagriCore with the GLP-1-receptor agonist SemaCore^3,7. The research literature attributes its effects mainly to the complementary actions of amylin-receptor and GLP-1-receptor agonism on glycaemic control and body weight⁷. CagriCore was developed as a stable, lipidated amylin analogue because native amylin readily forms amyloid fibrils¹²; in SemaCore, a fatty-acid moiety attached through a linker secures high albumin affinity and prolonged exposure¹³. The combination has been studied in phase 1b and phase 2 trials^3,4, in phase 3 trials in adults with overweight or obesity with or without type 2 diabetes (REDEFINE 1, 2 and 5) and in type 2 diabetes (REIMAGINE 1, 2 and 3)^1,2,5,6,7,8, in two secondary analyses of REDEFINE 1^9,10 and in diet-induced obese rats¹¹.

Evidence base: Ten human records of the combination itself: a randomised phase 1b trial (n = 96, 20 weeks)⁴, a randomised phase 2 trial against each component alone (n = 92, 32 weeks)³, six randomised, double-blind phase 3 trials (n = 189 to 3,417; 40 to 68 weeks)^1,2,5,6,7,8 and two secondary analyses of REDEFINE 1^9,10. Single-component arms were part of REDEFINE 1, REIMAGINE 2 and the phase 2 trial, and REDEFINE 5 used SemaCore alone as comparator^1,3,5,7. Preclinical data come from a controlled rat study¹¹ and a rat study of treatment discontinuation (Petersen 2026, PMID 42951207). The components alone were studied in separate trials (Lau 2021, PMID 34798060; Wilding 2021, PMID 33567185). No study of a research blend of the two peptides was identified: the trials used co-administered or fixed-dose combination trial products^3,4,9.

• CagriCore. Lipidated 37-residue amylin analogue with a C20 fatty diacid attached through a γ-glutamic acid linker at the N-terminus and a disulfide bridge between Cys2 and Cys7 (CAS 1415456-99-3); selected from structure-activity work on amylin analogues¹².
• SemaCore. Acylated 31-residue GLP-1 analogue with a C18 fatty diacid attached through a γ-glutamic acid and two 8-amino-3,6-dioxaoctanoic acid units (CAS 910463-68-2); two amino-acid substitutions compared with human GLP-1 (Aib8, Arg34), derivatised at lysine 26¹³.

Key studies at a glance

Phase 2 outcomes by group in type 2 diabetes (Frias 2023 [S3])

Effects reported in the studies

• Body weight without diabetes (REDEFINE 1). In adults with overweight or obesity without diabetes (n = 3,417), body weight changed by -20.4 % with CagriSema vs. -3.0 % with placebo to week 68 (difference -17.3 percentage points, p < 0.001; treatment-policy estimand), and weight-loss targets of 5 %, 20 %, 25 % and 30 % or more were reached more often¹. Both a BMI < 27 kg/m² and a waist-to-height ratio < 0.53 were reached by 30.3 %, 19.1 %, 9.0 % and 3.3 % (CagriSema, SemaCore alone, CagriCore alone, placebo) in a post hoc analysis⁹.
• Combination vs. single components. REDEFINE 1 (trial product estimand): -22.7 % with CagriSema, -16.1 % with SemaCore alone, -11.8 % with CagriCore alone and -2.3 % with placebo at week 68^9,10. Phase 2: a greater weight change with CagriSema than with either component (p < 0.0001 each; values in the table above)³. REDEFINE 5 (n = 331): -18.4 % vs. -11.9 % with SemaCore alone (difference -6.5 percentage points, p < 0.0001)⁵.
• Body weight with type 2 diabetes. REDEFINE 2 (n = 1,206): -13.7 % vs. -3.4 % with placebo at week 68 (p < 0.001)²; REIMAGINE 1: -13.8 % and -11.8 % at the higher and lower dose level vs. -1.4 % at week 40 (p < 0.0001)⁶; REIMAGINE 3 (on basal insulin): reductions of 10-12 %, without a placebo value in the abstract⁸.
• Glycaemic measures. In phase 2 the HbA1c change with CagriSema was greater than with CagriCore (difference -1.3 percentage points, p < 0.0001) but not significantly different from SemaCore (-0.4, p = 0.075); fasting plasma glucose likewise differed from CagriCore (p = 0.0010) but not from SemaCore (p = 0.10)³. REIMAGINE 2: -1.91 vs. -1.75 percentage points with the higher-dose SemaCore arm (difference -0.16, p = 0.0035)⁷. REDEFINE 2: HbA1c of 6.5 % or less in 73.5 % vs. 15.9 % with placebo².
• Blood pressure (REDEFINE 1). Systolic -10.9 vs. -2.8 mm Hg and diastolic -5.4 vs. -1.7 mm Hg with CagriSema vs. placebo at week 68; blood-pressure targets were reached by 63.0 % vs. 32.0 %; 39.6 % vs. 18.8 % of those using antihypertensive medication decreased or stopped it¹⁰.
• Pharmacokinetics (phase 1b). With all participants on SemaCore, CagriCore exposure was proportional to its dose and did not affect SemaCore exposure or elimination; half-lives were 159-195 h (CagriCore) and 145-165 h (SemaCore). At week 20, weight loss was 15.4-17.1 % in three CagriCore cohorts vs. 8.0-9.8 % with placebo, all on SemaCore⁴.
• Energy balance in rats. In diet-induced obese male rats, CagriSema produced about 12 % vehicle-adjusted weight loss with a 39 % lower energy intake, whereas weight-matched rats needed a 51 % reduction (p = 0.03); energy expenditure was similar to vehicle with CagriSema but 17 % lower in weight-matched rats (p = 0.008), so that 28 % of the weight loss was attributed to energy expenditure and 72 % to energy intake¹¹. After discontinuation, rats showed hyperphagia and rapid weight regain (Petersen 2026, PMID 42951207).

Adverse effects and tolerability reported

• Gastrointestinal events. Reported in REDEFINE 1 in 79.6 % with CagriSema vs. 39.9 % with placebo (nausea, vomiting, diarrhoea, constipation or abdominal pain), mainly transient and mild to moderate¹; in REDEFINE 2 in 72.5 % vs. 34.4 %, mostly transient and mild or moderate².
• Comparisons with the single components. REIMAGINE 2: any adverse event in 86.9 % with CagriSema vs. 81.2 % with SemaCore (both higher dose level), 82.2 % with CagriCore and 70.5 % with placebo; gastrointestinal disorders were the most common in the active groups⁷. REDEFINE 5: 87 % vs. 84 % with SemaCore alone (gastrointestinal 53 % vs. 51 %); 10 % vs. 6 % discontinued treatment⁵. CagriCore alone: gastrointestinal events in 41-63 % vs. 32 % with placebo (Lau 2021, PMID 34798060).
• Phase 2 and phase 1b. Phase 2: mild or moderate gastrointestinal events were the most common, with no level 2 or 3 hypoglycaemia and no fatal adverse events³. Phase 1b: 566 adverse events in 92 participants, 207 (37 %) of them gastrointestinal; most were mild to moderate, and the proportion with adverse events was similar across groups⁴.
• Hypoglycaemia and deaths. REIMAGINE 3 (on basal insulin): no severe hypoglycaemia; adverse events in 80 % and 71 % vs. 71 % with placebo, mostly mild or moderate gastrointestinal; one death not related to treatment (malignancy)⁸. REIMAGINE 1: 79 % and 75 % vs. 66 %, mostly mild or moderate and gastrointestinal⁶. REDEFINE 5: one death with SemaCore alone, not judged treatment related⁵.
• Hypotension. In REDEFINE 1, hypotension was reported in 38 (1.8 %) participants with CagriSema vs. 3 (0.4 %) with placebo¹⁰.
• Data not reported. The controlled rat study reports no adverse-event data¹¹ and the post hoc target analysis no safety data⁹; for most trial reports only the abstract was evaluated, so event rates beyond the abstracts are not given here.

Limitations of the evidence. All cited trials and the controlled rat study were funded by the developer, the rat study in part also by a public grant^{1,2,3,4,5,6,7,8,9,10,11}; no independent trial is among the cited records. The trial products were co-administered or fixed-dose combinations, not a research blend of the two peptides^3,4,9; equal mass of the two components is not an equimolar ratio. The single-component arms of REDEFINE 1 were much smaller (302 each vs. 2,108 with CagriSema), and the values given here for them come from the secondary publications (trial product estimand), as the abstract of the primary report does not state them^1,9,10. REIMAGINE 2 gives no body-weight values in its abstract and REIMAGINE 3 only a range^7,8. Rat data (males only)¹¹ cannot be generalised to humans, and data on discontinuation come from rats only (Petersen 2026, PMID 42951207). No cardiovascular outcome results for the combination are among the cited records. None of the findings summarised here establish efficacy or safety for any use outside the described research models.

References

1. Garvey WT, Blüher M, Osorto Contreras CK, Davies MJ, Winning Lehmann E, Pietiläinen KH, Rubino D, Sbraccia P, Wadden T, Zeuthen N, Wilding JPH; REDEFINE 1 Study Group (2025). Coadministered Cagrilintide and Semaglutide in Adults with Overweight or Obesity. The New England Journal of Medicine. PMID 40544433 DOI human study
2. Davies MJ, Bajaj HS, Broholm C, Eliasen A, Garvey WT, le Roux CW, Lingvay I, Lyndgaard CB, Rosenstock J, Pedersen SD; REDEFINE 2 Study Group (2025). Cagrilintide-Semaglutide in Adults with Overweight or Obesity and Type 2 Diabetes. The New England Journal of Medicine. PMID 40544432 DOI human study
3. Frias JP, Deenadayalan S, Erichsen L, Knop FK, Lingvay I, Macura S, Mathieu C, Pedersen SD, Davies M (2023). Efficacy and safety of co-administered once-weekly cagrilintide 2·4 mg with once-weekly semaglutide 2·4 mg in type 2 diabetes: a multicentre, randomised, double-blind, active-controlled, phase 2 trial. The Lancet. PMID 37364590 DOI human study
4. Enebo LB, Berthelsen KK, Kankam M, Lund MT, Rubino DM, Satylganova A, Lau DCW (2021). Safety, tolerability, pharmacokinetics, and pharmacodynamics of concomitant administration of multiple doses of cagrilintide with semaglutide 2·4 mg for weight management: a randomised, controlled, phase 1b trial. The Lancet. PMID 33894838 DOI human study
5. Yamauchi T, Becker NP, Hagemann CA, Huang KC, Kiyosue A, Lim S, Onishi Y, Kosuvaripalli A, Takano T, Ishigaki Y; REDEFINE 5 study group (2026). Efficacy and safety of co-administered cagrilintide and semaglutide versus semaglutide alone in adults with overweight or obesity with or without type 2 diabetes in Japan and Taiwan (REDEFINE 5): a multicentre, randomised, active-controlled, phase 3a trial. The Lancet Diabetes & Endocrinology. PMID 42009015 DOI human study
6. Aroda VR, Buzzetti R, Dalskov SM, Jain AB, Larsen JH, Mathieu C, Pratley RE, Videmark A, Watt T, Buse JB (2026). Efficacy and safety of once-weekly cagrilintide-semaglutide (CagriSema) in adults with type 2 diabetes inadequately controlled on diet and exercise (REIMAGINE 1): a randomised, double-blind, placebo-controlled, phase 3a study. The Lancet Diabetes & Endocrinology. PMID 42251860 DOI human study
7. Buse JB, Bajaj HS, Dalskov SM, Donaldson L, Hansen Duus HH, Fabricius TW, Haluzík M, Lingvay I, Pedersen SD, Pratley RE, Jain AB; REIMAGINE 2 study group (2026). Cagrilintide-semaglutide (CagriSema) versus semaglutide or cagrilintide in people with type 2 diabetes (REIMAGINE 2): a double-blind, randomised, controlled, phase 3 study. The Lancet Diabetes & Endocrinology. PMID 42251859 DOI human study
8. Rosenstock J, Billings LK, Gajria R, Giorgino F, Johansen NB, Klein KR, Thamattoor UK, Buse JB, Jain AB (2026). Cagrilintide-semaglutide (CagriSema) as an add-on to basal insulin in adults with type 2 diabetes (REIMAGINE 3): a randomised, double-blind, placebo-controlled, multicentre, phase 3 study. The Lancet. PMID 42251856 DOI human study
9. Busetto L, Contreras CO, Christensen MH, Garvey WT, Horn DB, McGowan B, Miller CP, Schnecke V, le Roux CW (2026). Efficacy of CagriSema for Reaching Anthropometric Treatment Targets and Cardiometabolic Outcomes: A Secondary, Post hoc Analysis of REDEFINE 1. Diabetes, Obesity and Metabolism. PMID 42503495 DOI human study
10. Verma S, Böttcher M, Brown P, Dicker D, Rubino D, Sbraccia P, Sharma AM, Smedegaard L, Sørrig R, Garvey WT (2026). CagriSema Reduces Blood Pressure in Adults With Overweight or Obesity: REDEFINE 1. Hypertension. PMID 41328546 DOI human study
11. Jacobsen JM, Halling JF, Blom I, Moreno Martinez J, Hald B, Pedersen K, Fels JJ, Snitker S, Secher A, Lundh S, le Roux CW, Raun K, Reitman ML, Kuhre RE (2025). CagriSema drives weight loss in rats by reducing energy intake and preserving energy expenditure. Nature Metabolism. PMID 40629149 DOI
12. Kruse T, Hansen JL, Dahl K, Schäffer L, Sensfuss U, Poulsen C, Schlein M, Hansen AMK, Jeppesen CB, Dornonville de la Cour C, Clausen TR, Johansson E, Fulle S, Skyggebjerg RB, Raun K (2021). Development of Cagrilintide, a Long-Acting Amylin Analogue. Journal of Medicinal Chemistry. PMID 34288673 DOI
13. Lau J, Bloch P, Schäffer L, Pettersson I, Spetzler J, Kofoed J, Madsen K, Knudsen LB, McGuire J, Steensgaard DB, Strauss HM, Gram DX, Knudsen SM, Nielsen FS, Thygesen P, Reedtz-Runge S, Kruse T (2015). Discovery of the Once-Weekly Glucagon-Like Peptide-1 (GLP-1) Analogue Semaglutide. Journal of Medicinal Chemistry. PMID 26308095 DOI

This section summarises findings published in the cited peer-reviewed literature for informational purposes. It is not a claim of efficacy or safety, contains no dosing or administration information by design, and does not constitute medical, veterinary or scientific advice. Results in cell cultures or animal models do not predict effects in humans.